Phthalidyl esters of 7-[(α amino, 2 substituted acetamido)-3-(heterocyclic-thio methyl)]cephalosporins

ABSTRACT

Phthalidyl and substituted phthalidyl esters of certain cephalosporins are absorbed by the oral route into the serum, where they are hydrolyzed to the parent antibacterially active cephalosporin.

CROSS-REFERENCE

This is a division of Ser. No. 549,374 filed Feb. 12, 1975, nowabandoned.

This invention relates to phthalidyl and certain substituted phthalidylesters of cephalosporins, and to a method for their preparation. Suchesters are valuable in that they are absorbed by the oral route into theserum, where they are hydrolysed to release the parent antibacteriallyactive cephalosporin.

According to the present invention there is provided a cephalosporinester of formula (I) and pharmaceutically acceptable acid addition saltsthereof: ##STR1## wherein R is a phenyl, 4-hydroxyphenyl,3,4-dihydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2- or 3- thienyl ordihydrophenyl group; X is an acetoxy, carbamoyloxy or heterocyclic thiogroup; and R¹ and R² are hydrogen or methoxy groups, provided that whenR¹ and R² are both hydrogen and X is acetoxy, then R is not phenyl.

Suitable acid addition salts of the compounds of formula (I) include,for example, inorganic salts such as the sulphate, nitrate, phosphate,borate and hydrohalides, e.g., hydrochloride, hydrobromide andhydroiodide and organic salts such as the acetate, oxalate, tartrate,maleate, citrate, succinate, benzoate, ascorbate and methanesulphonate.

The group X may be inter alia a heterocyclic thio group. Examples ofparticular X groups include the following: ##STR2##

Preferably, the group X is (2-methyl-1,3,4-thiadiazol-5-yl) thio,(1-methyl-(1H)-1,2,3,4-tetrazol-5-yl) thio,(2-methyl-1,3,4-oxadiazol-5-yl) thio, or (1H-1,3,4-triazol-5-yl) thio.

The compounds of formula (I) may be prepared by reacting a compound offormula (II): ##STR3## or a reactive esterifying derivative thereof,wherein R and X are as defined with respect to formula (I), with acompound of formula (III): ##STR4## or a reactive esterifying derivativethereof, wherein R¹ and R² are as defined with respect to formula (I)and wherein any reactive groups such as amino and hydroxy may beblocked, and thereafter, if necessary:

(i) converting a Δ² isomer into the desired Δ³ isomer;

(ii) removing any blocking group in the acyl side chain.

By "reactive esterifying derivative" in relation to compounds (II) and(III) above, we mean derivatives of (II) and (III) which when reactedtogether take part in a reaction with the consequent formation of anester linkage of formula (I). Many methods of esterification are knownfrom the literature. For example, the esterification reaction definedabove may be achieved by reacting an N-protected cephalosporanic acid offormula (II) or a salt thereof with a 3-halophtholide or3-halo-5,6-dimethoxyphthalide. Examples of suitable salts include alkalimetal salts such as sodium or potassium, or a trialkylammonium salt suchas triethylammonium.

With this route it is preferable to protect the α-amino group in theside chain of compound (I) prior to the esterification reaction. In suchcases any of the amino protecting groups known from the literature onthe synthesis of α-aminobenzyl penicillin or α-aminobenzylcephalosporanic acids are suitable.

Examples of protected amino groups include the protonated amino group(NH⁺ ₃) which after the acylation reaction can be converted to a freeamino group by simple neutralization; the t-butyloxycarbonyl,benzyloxycarbonylamino group or substituted benzyloxycarbonyl-aminogroups which are subsequently converted to NH₂ by catalytichydrogenation; and various groups which after the acylation reactionregenerate the amino group on mild acid hydrolyzis. (Alkaline hydrolyzisis not generally useful since hydrolyzis of the ester group takes placeunder alkaline conditions.

Example of a protected amino group which may subsequently be convertedto NH₂ by mild acid hydrolyzis include enamine groups of general formula(IV) or tautomeric modifications thereof, and α-hydroxyarylidene groupsof general formula (V) or tautomeric modifications thereof: ##STR5##

In structures (IV) and (V) the dotted lines represent hydrogen bonds. Instructure (IV) R³ is a lower alkyl group, R⁴ is either a hydrogen atomor together with R³ completes a carbocyclic ring, and R⁵ is a loweralkyl, aryl, or lower alkoxy group. In structure (V) Z represents theresidue of a substituted or unsubstituted benzene or naphthalene ring.

An example of a "protected amino" which can be converted to NH₂ afterthe esterification reaction is the azido group. In this case, the finalconversion into NH₂ may be brought about by either catalytichydrogenation or electrolytic reduction. Alternatively the amino groupmay be blocked as the nitro group which is later converted to the aminogroup by reduction.

In the above process, the esterification reaction may cause a doublebond shift to position 2 of the cephem nucleus, thereby producing amixture of 2-cephem and 3-cephem isomers. If this happens, the2-cephem/3-cephem mixture can be converted to the 3-cephem isomer byoxidation of the mixture to the sulphoxide followed by reduction. Thisis, of course, a standard method for the preparation of 3-cephems from2-cephems, and is described for example in British Pat. No. 1,280,693.One such method is treatment with triphenylphosphine and acetylchloride.

The compounds of this invention may also be prepared by reacting acompound of formula (VI) ##STR6## wherein the dotted line represents abond in the 2- or 3-position and n is 0 or 1 with a reactive N-acylatingderivative of an acid of formula (VII): ##STR7## wherein R, R¹, R² and Xare as defined in formula (I) and wherein any reactive groups, such asamino and hydroxy groups may be blocked, and thereafter, if necessarycarrying out one or more of the following steps:

(i) converting a Δ² isomer into the desired Δ³ isomer;

(ii) reduction of a sulphoxide compound to form the desired sulphidecompound;

(iii) removal of any blocking groups in the acyl side chain;

A reactive N-acylating derivative of the acid (VII) is employed in theabove process. The choice of reactive derivative will of course beinfluenced by the chemical nature of the substituents in the acid.

Suitable N-acylating derivatives include an acid halide, preferably theacid chloride, or a mixed anhydride. For this purpose particularlyconvenient mixed anhydrides are the alkoxyformic anhydrides.

Alternative N-acylating derivatives of acid (VII), are activated esters.Such activated esters, for example the ester formed with1-hydroxybenztriazole or N-hydroxysuccinimide, may be prepared in situby the reaction of the acid with the appropriate hydroxy compound in thepresence of a carbodiimide, preferably dicyclohexylcarbodiimide.

Other reactive N-acylating derivatives of the acid (VII) include thereactive intermediate formed by reaction in situ with a carbodiimide orcarbonyldiimidazole, but the literature on the preparation ofsemi-synthetic penicillins contains examples of other reactiveN-acylating derivatives of acids suitable for coupling to 6-APA, forexample the acid azide.

Again any of the known N-protecting groups may be employed (especiallythe t-butoxyoarbonyl group).

Compounds of formula (I) wherein X is a heterocyclic thio group may beprepared by displacing the acetoxy group from the corresponding3-acetoxymethyl compound of formula (I) (i.e., X═acetoxy) bynucleophilic displacement thiol.

The compounds of this invention, wherein X is carbamoyloxy, may also beprepared from the corresponding 3-hydroxymethyl compound bycarbamoylation of the hydroxy group. In such a process, a compound offormula (VIII): ##STR8## wherein the dotted line represents a bond inthe 2- or 3-position, n is 0 or 1, R, R¹ and R² are as defined informula (I), and wherein any reactive groups may be blocked, is reactedwith an isocyanate of formula R⁶ NCO where R⁶ is a group which isremovable from the reaction product with compound (VIII) under mildconditions to give compound (I) and thereafter, if necessary, one ormore of the following steps is carried out:

(i) converting a Δ² isomer into the desired Δ³ isomer;

(ii) reduction of a sulphoxide compound to form the desired sulphidecompound; and

(iii) removal of any blocking groups in the acyl side chain;

Examples of compounds of formula R⁶ NCO are disclosed in Belgian Pat.No. 794389. Suitable examples include trimethylsilyl isocyanate,β,β,β-trichloroethylisocyanate, and chlorosulphonyl isocyanate. Thelatter is preferred.

The intermediates of formula (VIII) may be prepared by the action of anesterase, for example citrus acetyl esterase, on the corresponding3-acetoxymethyl cephem, [(I), X=OCOCH₃ ].

The following Examples illustrate the preparation of some of thecompounds of this invention:

EXAMPLE 1 Phthalidyl 7-(2-thienylacetamido)-cephalosporanate (Epimers Aand B) Method (a)

3-Bromophthalide (53.2g., 0.25 mole) was added to a stirred suspensionof sodium 7-(2-thienylacetamido)-cephalosporanate (104.5g., 0.25 mole)in dry D.M.F. (850 mls) at 0°- 5°. After 65 mins. at 20° the almostclear solution was added to ice-water (12 liter) and the precipitatedsolid collected and washed with 2% NaHCO₃ solution, water, drying andevaporating, the crude product was reprecipitated from aqueous methanoland then refluxed in methanol for 15 mins. After cooling the insolubleepimer A (19.0g., 15%) m.p. 172°-5° was collected. A sample foranalysis, m.p. 175.8° [α]_(D) ²⁵ = -40.8° (C=0.72, acetone) wascrystallized twice from methanol: λ_(max) ^(KBr) 1780 (b), 1735, 1670,1530, 1230, 975 cm⁻¹ ; _(max) ^(Dioxan) 272.5nm (ε, 8150) and 280nm (ε,7,600) (shoulder). δ(CDCl.sub. 3 : 2.10) (s, 3H, CH₃) 3.51 and 3.56(main peaks of ABq, 2H, --S--CH₂), 3.88 (s, 2H, --CH₂ CO), 4.96(d,J=4.7Hz, C6--H) and 5.03, 5.12 (main peaks of ABq, --CH₂ --O) (3H inall), 5.85 (q,J₆,7 -4.7Hz., J₇,NH -9Hz.,1H, C7-H), 6.52 (d,1H,NH),7.0-8.1 (m, 8H, Ar-H and --O--CH--O--).

Found C, 54.62; H, 3.91; N, 5.13; C₂₄ H₂₀ N₂ S₂ O₈ (528) (requiresC,54.54; H,3.81N, 5.30%.

The mother liquors from the reaction contained further quantities of thephthalidyl ester as a mixture of Δ³ and Δ² isomers. Further quantitiesof the Δ³ -isomer were isolated after oxidation-reduction as describedbelow:

(i) Phthalidyl 7-(2-thienylacetamido)-cephalosporanate sulphoxide;

A mixture of phthalidyl 7-(2-thienylacetamido) cephalosporanate and itsΔ² isomer (14.4g) was dissolved in alcohol-free chloroform (230 mls) at0°-5° and a solution of 3-chloroperbenzoic acid (5.09g) in chloroform(97 mls) was added over 15 mins. After 5 hours at 25°, the solution waswashed with N-NaHCO₃, water, dried and evaporated.

The crude product was refluxed with methanol (100 mls) for 1 hour andthe desired sulphoxide (10.3g, 70%) collected. λ_(max) ^(KBr) 1790 (b),1740, 1680, 1515, 1230, 1050, 975 cm⁻¹. λ_(max) ^(Dioxan) 275nm (ε8220);δ [(CD₃)₂ SO] 2.04 (s,3H, CH₃), 3.8 and 3.93 (main peaks of ABq, C2-H)and 3.87 (s, CH₂ CO) (4H in all); 4.8 and 5.1 (main peaks of ABq, CH₂ O)and 4.87, 4.96 (d,J=4, C6-H) (3H in all), 5.9 (m, 4 lines, J₇,NH = 8,J₆,7 = 4, 1H, C₇ -H), 7.0-8.0 (m,8H, Ar-H and O--CH--O) and 8.4 (d, J =8, NH).

Found C, 52.6; H, 3.7; N, 5.0; Calculated for C₂₄ H₂₀ N₂ O₉ S₂ (544): C,52,9; H, 3.7; N, 5.1%.

(ii) Reduction of Sulphoxide

The sulphoxide (7.5g, 13.8 mole) was dissolved in D.M.F. (60 ml) andtreated with triphenylphosphine (7.2g) and acetyl chloride (3.4 ml) at0°-5°. After 11/2 hours the pale yellow solution was treated with moretriphenylphosphine (1.8g) and stirring continued for 1/2 hour more. Icewater (300 mls) and N--NaHCO₃ (100 mls) were then added and the mixtureextracted with ethyl acetate (3 times).

These extracts were washed with water, dried and evaporated and theresulting brown residue triturated with ether repeatedly to removeexcess triphenylphosphine. The insoluble residue was taken up intomethanol, decolourised with activated charcoal and the filtrate allowedto crystallize. After refridgeration the insoluble solid (3.1g) wascollected and addition of water to the liquors provided a second crop(4.4). Residual triphenyl-phosphine was freed from the combined materialby trituration with ether to give the desired ester (4.2g, 58%) as amixture of epimers A and B.

Method (b)

A solution of 7-(2-thienylacetamido) cephalosporanic acid (from 2.1g, 5mmole of the sodium salt), phthalaldehydic acid (0.75g) anddicyclohexylcarbodiimide (1.03g) in methylene dichloride (30 mls). After4 hours at 0°-5° the insoluble solid was filtered and the filtrateswashed with NaHCO₃ water, dried and evaporated. Chromatography of theresidue provided epimer B (0.54g, 20%) m.p. 169°-171°. [α] D²⁵ + 43.4(C,0.94, acetone), after crystallisation from methanol. δ (CDCl₃): 2.06(s, 3H, CH₃), 3.47 and 3.53 (main peaks of ABq, 2H, S--CH₂) 3.87 (s, 2H,CH₂ CO), 4.7-5.3 (d and ABq, 3H, C6-H and CH₂ O), 5.85 (dd, 1H, C7-H),6.6 (d,NH), 7.0-8.0 (m, 8H, ArH and O--CH--O).

Found. C, 54.4; H, 3.9; N, 5.3. Calculated for C₂₄ H₂₀ N₂ S₂ O₈ : C,54.5; H, 3.8; N, 5.3%.

EXAMPLE 2 (a) Phthalidyl7-D-α-t-butyloxycarbonylaminophenylacetamido-3-(2'-methyl-1', 3',4'-thiadiazol-5'-yl-thiomethyl) ceph-3-em-4-carboxylate

7-D-α-t-butyloxycarbonylphenylacetamido-3-(2'-methyl-1', 3',4'-thiadiazol-5'-yl-thiomethyl) ceph-3-em-4-carboxylic acid, (3.00g) wasdissolved in dry DMF (30 mls) at 0°-5° and treated with Et₃ N (0.96 ml)and then bromophthalide (1.62g) dissolved in DMF (10 mls), was added.After 30 mins. at 0°-5° and 1 hour at 20°, the solution was poured intowater (800 mls). The precipitated solid was washed well with water,dissolved in ethyl acetate and this solution washed with sodiumbicarbonate, water, dried and evaporated. Precipitation from EtAc-petrolprovided the desired ester as a buff colored solid (2.3g, 47%).

This material was used without further purification. λ_(max) ^(CHCl).sbsp.3 3380, 1785 (b), 1700 (shoulder), 1960, 1485, 1160, 980cm⁻¹λ_(max) ^(EtOH) 228nm )ε, 18590) and 268 nm (ε, 12620). δ (CDCl₃) 1.40(s,9H, Bu-H), 2.71 (s, 3H, thiadiazolyl-CH₃), 3.5-4.4 (m, 4H in all,S-CH₂), 4.9 (d), 5.2 (m), and 5.7 (m) (Cα, C₆ and C₇ -H), 7.3-8.0 (m,Ar--H, O--CH--O and NH).

(b) Phthalidyl 7-D-α-aminophenylacetamido-3-(2'-methyl-1', 3',4'-thiadiazol-5'-yl-thiomethyl) ceph-3-em4-carboxylate

The t-butoxycarbonyl derivative (1.50g) was treated at 5°-0.0° with 98%aqueous trifluoroacetic acid (15 mls) for 1 hour, when the solution wasevaporated. Trituration of the residue with ether provided theessentially pure TFA salt (1.4g) λ_(max) ^(CHCl).sbsp.3 3400 - 2600,1785 (b), 1700 (shoulder), 1675, 1620, 1540, 1190, 1140, 980 cm⁻¹ _(max)^(EtOH) 227nm (ε, 16690) and 268nm (ε, 12020).

Neutralization of the TFA salt yielded the free amino ester.

EXAMPLE 3 (a) Phthalidyl7-(D-α-t-butyloxycarbonylamino-p-hydroxy-phenylacetamido)-cephalosporanate

The mixed anhydride was prepared fromt-butyloxycarbonyl-D-p-hydroxyphenylglycine (2.53g, 9.50mmole),triethylamine (1.33 ml, 9.50mmole) and isobutylchloroformate (1.24 ml,9.50mmole) at -10° to -15° in dry T,H,F. (30 mls) and CH₂ Cl₂ (5 mls).After stirring for 10 mins. at this temperature a solution of ACAphthalide ester hydrochloride (4.18g, 9.50mmole) in CH₂ Cl₂ 935 mls)containing triethylamine (1.33 ml) was added in one portion over 5 mins.maintaining the temperature at <10°. The reaction was worked up in theusual way. The crude product (4.81g, 78%) which was precipitated fromethyl acetate-petrol ether, was purified from some contaminatingphthalide-7-isobutyloxycarbonyl-p-hydroxphenylacetamidocephalosporanateby chromatography on silica gel. The desired ester (2.5g) m.p. 126°-131°dec; had the following characteristics: λ_(max) ^(CHCl).sbsp.3 3380,3300, 1780, 1740, 1685, 1495, 1365, 1220, 980cm⁻¹. λ_(max) ^(EtOH) 230nm(c, 20, 860) and 273nm (ε,9170). δ [(CD₃)₂ SO]1.38 (s, 9H,Bu-H), 2.0 (s,3H, CH₂, OO), 3.56, (bs, 2H,S-CH₂), 4.6-5.3 (m, ˜4H, Cα-, C6- and OCH₂),5.7 (m, 1H, C7-H), 6.6, 6.75, 7.16 and 7.3 (dd, 4H, p-HO--C₆ H₄),7.5-8.1 (m, 5H, O--CH--O and phthalide-H). 9.0 (m, ˜2H, NH) and 9.32 (s,1H, OH).

Found: C. 56.1; H, 4.8; N, 6.1. Calculated for C₃₁ H₃₁ N₃ O₁₁ S (654):C,56.9; H,4.8; N, 6.4%=

(b) Phthalidyl 7-(D-α-amino-p-hydroxylphenylacetamido)-cephalosporanatetrifluoroacetate

The protecting t-butyloxycarbonyl group was cleaved from the precedingderivative by treatment with 98% aqueous trifluoracetic acid over 1hour. The desired trifluoroacetate, m.p. 144-8° dec. was obtained in 92%yield as an amorphous solid: λ_(Max) ^(EtoH) 232nm (ε,20,625) and 273nm(ε,8740). δ [(CD₃)₂ SO] 2.02 (s, 3H, CH₃ CO), 3.6 (bs, 2H, S--CH₂),4.7-5.2 (m, ˜4H, Cα-, C6- and O--CH₂) 5.8 (m, 1H, C7--H), 6.75, 6.9, 7.3and 7.4 (dd, 4H, p--HO--C₆ H₄). 7.5-8.1 (m, --O--CH--O and phthalide --Hand OH) 8.7 (m, 3H, NH₃ ⁺) and 9.5 (m, NH).

Found: C, 47.8; H, 3.6; N, 5.7. Calculated for C₂₈ H₂₄ N₃ O₁₁ SF₃ 2H₂ OC, 47.8; H, 4.0; N, 6.0%.

EXAMPLE 4

By substituting 3-bromo-5,6-dimethoxyphthalide for 3-bromophthalide inthe same procedure as in Examples 1, 2 and 3 the following compounds areobtained:

5¹,6¹ -Dimethoxyphthalidyl 7-(2-thienylacetamido) cephalosporanate.

5¹,6¹ -Dimethoxyphthalidyl-7-(D-a-aminophenylacetamido)-cephalosporanatehydrochloride.

5¹,6¹ -Dimethoxyphthalidylcephaloglycinate

5¹,6¹ -Dimethoxyphthalidyl7(D-α-amino-p-hydroxyphenylacetamido)cephalosporanate.

5¹,6¹ -Dimethoxyphthalidyl7[D-α-aminophenylacetamido-3-(2-methyl-1¹,3¹,4¹-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate.

EXAMPLE 5 (a) Phthalidyl7-D-α-t-butyloxycarbonylaminophenylacetamido-3-(1¹ -methyl-1¹-H-tetraxol-5¹ -ylthiomethyl)ceph-3-em-4-carboxylate

Sodium 7-D-α-t-butyloxycarbonylaminophenylacetamido-3-(1¹ -methyl-1¹-H-tetraxol-5¹ -ylthiomethyl)ceph-3-em-4-carboxylate (2.4g, 4.1mmole)was stirred in dry DMF (30 ml) and bromophthalide (0.85g, 4mmole) addedwith ice cooling. After 3 hours at 20° the mixture was poured intoice-water (300 ml) and the solid collected. An ethyl acetate solution ofthe latter was washed with dilute sodium bicarbonate, water, dried andevaporated. Precipitation of the residue from ethyl acetate - petrolprovided the desired ester (2.0g, 74%), which was used without furtherpurification. λ_(Max) ^(EtOH) 270nm (c, 7750); λ_(max) ^(CHCL).sbsp.33400, 1790, 1740, 1700(b), 1495, 1165, 980cm⁻¹.

Alternatively the crude product could be separated by silica gelchromatography into the 3-epimers.

(b) Phthalidyl 7-D-α-aminophenylacetamido-3-(1¹ -methyl-1¹-H-tetrazol-5¹ -yl-thiomethyl)ceph-3-em-4-carboxylate

The preceding t-butyloxycarbonyl derivative (2.5g, 3.6mmole) was stirredfor 0.75 hour at 10° with trifluoracetic acid (25 mls). Afterevaporation of the latter the residue was triturated with dry ether andthe crude trifluoracetate of the title compound (2.48g, 97%) wascollected and washed well with ether. The product showed one main zoneon biochromatography, R_(f) = 0.85 in n-butanol-ethanol-water. ν_(max)^(nujol) 1785, 1680, 1200cn⁻¹. δ (DMSO) 3.4 - 4.1 (m, 2H, C2-H); 3.77and 3.92 (2s, 3H, tetraxolyl-CH₃), 4.1 0 4.6 (m, 2H, CH₂ S), 4.8 - 6.1(m, 3H, C6, C7 and Cα-H), 7.2 - 8.2 (m, 10H, Ar-H + OCHO). 8.9 (bs, 3H,NH₃ ⁺), 9.4 - 10.0 (m, NH); λ_(max) ^(EtOH) 270nm (ε, 7410 ).

EXAMPLE 6 (a) Phthalidyl7-D-α-t-butyloxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate

Sodium7-D-α-t-butyloxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate(2.1g, 4mmole) (see German OLS No. 2,550,151) is suspended in dry DMF(30 mls) and with ice cooling treated with bromophthalide (0.84g,0.39mmole). After 1 hour at 20° ice-water (300 mls) is added and thesolid collected. A solution of the latter in ethyl acetate is washeddilute sodium bicarbonate, water, dried and evaporated. Precipitation ofthe residue from ethyl acetate - petrol ether provides the desired ester(1.9g) which is used without further purification.

(b) Phthalidyl7-D-α-aminophenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate

The foregoing crude ester (1.6g) is treated with chilled trifluoroaceticacid (15 mls) over 40 mins. Evaporation and trituration with ether givesthe title compound as its trifluotacetate (1.5g). This shows one majorzone on biochromatography R_(f) = 0.75 in n-Butanol-water.

We claim:
 1. A cephalosporin ester of the formula ##STR9## or apharmaceutically acceptable acid addition salt thereof, wherein R isphenyl, 4-hydroxyphenyl, 3-chloro-4-hydrophenyl, 2- or 3-thienyl ordihydrophenyl; X is a heterocyclic thio group selected from the groupconsisting of ##STR10## (2-methyl-1,3,4-thiadiazol-5-yl) thio,(1-methyl-(1H)-1,2,3,4-tetrazol-5-yl) thio and (1H-1,3,4-triazol-5yl)thio; and R¹ and R² are both hydrogen or methoxy.
 2. A compoundaccording to claim 1 wheren X is (2-methyl-1,3,4-thiadiazol-5-yl) thio,(1-methyl-(1H)-1,2,3,4-tetrazol-5-yl) thio or (1H-1,3,4-triazol-5-yl)thio.
 3. The compound according to claim 1 which isphthalidyl-7-[D-α-aminophenylacetamido)-3-(2'-methyl-1',3',4'-thiadiazol-5'-yl)-thiomethyl]-ceph-3-em-carboxylate.4. The compound according to claim 1 which is5',6'-dimethoxyphthalidyl-7-[D-α-aminophenylacetamide-3-(2'-methyl-1',3',4'-thiadiazol-5-yl)-thiomethyl]-ceph-3-em-4-carboxylate.5. The compound according to claim 1 which isphthalidyl-7-[D-α-aminophenylacetamido-3-(1'-methyl'1'-H-tetrazol-5-yl)-thiomethyl]-ceph-3-em-4-carboxylate.6. A cephalosporin ester according to claim 1 in the form of an acidaddition salt selected from the group consisting of the sulphate,nitrate, phosphate, borate, hydrochloride, hydrobromide, hydroiodide,acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate,ascorbate and methanesulphonate.